Rainer H Müller

Freie Universität Berlin, Berlín, Berlin, Germany

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Publications (112)329.18 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: For the development of ultra-small NLC (usNLC) the determination of the required HLB (hydrophilic lipophilic balance) was found to be a suitable method, i.e., usNLC with a size below 50 nm were obtained by this method. Loading with 5% (w/w) coenzyme Q10 (Q10) led to usNLC with a size of about 85 nm. In comparison to classical NLC with a size of 230 nm and a nanoemulsion with similar size, the Q10 loaded usNLC show a higher release, a higher antioxidant capacity, and a better skin penetration for Q10. The reason for this is a flip–flop core–shell structure of the lipid matrix, i.e., the oil with dissolved active is surrounding the solid lipid based core. As the flip–flop structure was probably achieved by admixing high contents of liquid lipid, oil enriched usNLC might represent a novel and promising carrier system for the improved delivery of lipophilic actives.
    International Journal of Pharmaceutics 12/2014; 477(1). · 3.99 Impact Factor
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    ABSTRACT: UV irradiation leads to formation of reactive oxygen species (ROS). An imbalance between the antioxidant system and ROS can lead to cell damage, premature skin aging or skin cancer. To counteract these processes, antioxidants such as coenzyme Q10 (CoQ10) are contained in many cosmetics. To improve and optimize cell/ tissue penetration properties of the lipophilic CoQ10, ultra-small lipid nanoparticles (usNLC) were developed. The antioxidant effectiveness of CoQ10-loaded usNLC compared to conventional nanocarriers was investigated in the human keratinocyte cell line HaCaT. Using confocal laser scanning microscopy investigations of the carriers additionally loaded with nile red showed a clear uptake into cells and their distribution within the cytoplasm. By use of the XTT cell viability test, CoQ10 concentrations of 10 to 50μg/ ml were shown to be non-toxic, and the antioxidant potential of 10 μg/ml CoQ10 loaded usNLC in the HaCaT cells was analyzed via electron paramagnetic resonance spectroscopy after cellular exposure to UVA (1J/ cm(2)) and UVB (18mJ/ cm(2)) irradiation. In comparison to the CoQ10-loaded conventional carriers, usNLC-CoQ10 demonstrated the strongest reduction of the radical formation; reaching up to 23% compared to control cells without nanocarrier treatment. Therefore, usNLC-CoQ10 are very suitable to increase the antioxidant potential of skin. Copyright © 2014. Published by Elsevier B.V.
    12/2014;
  • Qionghua Wei, Cornelia M Keck, Rainer H Müller
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    ABSTRACT: The CapsMorph(®) technology prepares amorphous drugs for oral delivery by encapsulating them into porous materials. Hesperidin as model compound was loaded onto AEROPERL(®) 300 Pharma using the wetness impregnation method. Hesperidin was dissolved in dimethyl sulfoxide (DMSO) and alternatively in DMSO with addition of Tween 80. The drug solutions were added dropwise to the porous material and subsequently DMSO was evaporated. The AEROPERL(®) 300 Pharma could be loaded with about 30% hesperidin in the amorphous form. Amorphous state was verified by X-ray diffraction and differential scanning calorimetry. The CapsMorph(®) formulation was compared regarding properties determining oral bioavailability, i.e., kinetic saturation solubility and dissolution rate to raw drug powder and hesperidin nanocrystals. The saturation solubility of CapsMorph(®) without Tween 80 was 654μg/ml, which is 36-fold higher than the raw drug powder (18μg/ml) and about 20 times higher than nanocrystals (30μg/ml). In vitro release was faster (100% in 10min at pH 6.8) compared to dissolution of nanocrystals with about 15%. Addition of Tween 80 to CapsMorph(®) lowered the solubility (168μg/ml) and slowed down the release, but provided longer times of supersaturation without precipitation of drug. Based on these data, it appears that drug loaded porous materials provide better formulation compared to nanocrystals for poorly soluble drugs. Copyright © 2014. Published by Elsevier B.V.
    International Journal of Pharmaceutics 11/2014; · 3.99 Impact Factor
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    ABSTRACT: Industrial concentrates of hesperidin nanocrystals (5.0% nominal concentration) were produced applying the smartCrystal(®) combination technology of wet bead milling and subsequent high pressure homogenization. Stabilization was performed by Kolliphor(®) P 188, preservation by Euxyl PE 9010 and glycerol. Physical and chemical stability were monitored over 1.5 years of storage at 4-6°C. The size of the bulk population stayed unchanged with about 250nm (photon correlation spectroscopy). Absence of crystal growth by Ostwald ripening and absence of agglomerates were shown by laser diffraction (LD) and light microscopy. The LD diameter 90% was still 0.7μm after 1.5 years. Despite the large surface of the nanosuspension in contact with the water phase, the chemical content proved also stable, only a reduction by 0.15% from 5.70% to 5.55% content was observed. The nanocrystals kept their crystalline state unchanged as shown by X-ray diffraction. The saturation solubility of the nanosuspension was more than triple compared to the raw drug powder in water. The data show the availability of a stable hesperidin concentrate as intermediate for industry to produce dermal formulations. Copyright © 2014. Published by Elsevier B.V.
    International Journal of Pharmaceutics 11/2014; · 3.99 Impact Factor
  • Sven Staufenbiel, Christoph Weise, Rainer H. Müller
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    ABSTRACT: The organ distribution of intravenously injected nanoparticles is determined by the composition of the blood protein adsorption pattern occurring after injection. This is exploited in the concept of “differential protein adsorption” for drug targeting, which is briefly discussed. The surface properties of the nanoparticles determine the adsorption patterns, by controlling the surface properties one can generate adsorption patterns required for achieving the desired organ distribution. The efficiency of this principle is shown by reviewing different organ distributions achieved using various polymeric nanoparticles with different surface properties. Surface modification can be obtained by polymer adsorption and can create nanoparticles circulating in the blood, or accumulating in targets such as bone marrow and brain. The protein adsorption patterns were analyzed using two-dimensional polyacrylamide gel electrophoresis (2-D PAGE). Here, adsorption patterns of dendritic polymer nanoparticles were investigated, where the used polymer was dendritic polyglycerol sulfate. They showed reduced opsonization and preferential adsorption of apolipoprotein A-I with brain targeting potential. In perspective, the principle of surface property modification by polymer/stabilizer adsorption can be transferred to intravenous drug nanocrystals. A hybrid system of nanocrystal and polymeric nanoparticles is suggested, the polymeric nanoparticle with nanocrystal core.
    Macromolecular Symposia 11/2014; 345(1).
  • Sven Staufenbiel, Cornelia M. Keck, Rainer H. Müller
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    ABSTRACT: The surface hydrophobicity of nanoparticles is one factor determining blood protein adsorption after intravenous administration, thus the organ distribution. Hydrophobic surfaces lead to opsonization and uptake by the liver macrophages, when hydrophilic nanoparticles avoid this and can circulate in the blood. To predict, at least to a certain degree, the in vivo distribution, the surface hydrophobicity needs to be measured and quantified. Methods need to be used which quantify hydrophobicity of nanoparticles in liquid environment similar to the body situation (= real environment), not using e.g. dry methods from tabletting. Different of those methods are mentioned in this work. In the present study the hydrophobicity of differently coated azithromycin nanocrystals was analyzed with hydrophobic interaction chromatography (HIC) and aqueous two-phase partitioning (TPP). Investigated stabilizers were Poloxamer 188, Poloxamer 407, caprylyl/capryl polyglucoside (Plantacare® 810), decyl polyglucoside (Plantacare® 2000), polyethylene glycol (PEG)-20 sorbitan monooleate (Tween 80) and tocopheryl polyethylene glycol succinate. HIC results revealed that coating with PEG free Plantacares leads to more hydrophobic surfaces (e.g. Plantacare 2000 retention time (tr) = 17.0 ± 1.9 min and tr = 6.5 ± 0.1 min for Tween 80), when also an increase of the amount of polypropylene glycol (PPG) in the Poloxamers lead to a stronger retention. Furthermore, PEG containing samples were analyzed by TPP whereby HIC results could be confirmed. Additionally, TPP showed differences between stabilizers having only 1 PEG chain and stabilizers with more than 1 PEG chain. In perspective, these stabilizers leading to a low hydrophobicity are promising candidates for further in vivo studies due to a decreased opsonization.
    Macromolecular Symposia 11/2014; 345(1).
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    ABSTRACT: Alkyl polyglycosides (APGs) represent a group of nonionic tensides with excellent skin compatibility. Thus they seem to be excellent stabilizers for lipid nanoparticles for dermal application. To investigate this, different APGs were selected to evaluate their influence on the formation and characteristics of solid lipid nanoparticles (SLN). Contact angle analysis of the aqueous solutions/dispersions of the APGs on cetyl palmitate films revealed good wettability for all APG surfactants. Cetyl palmitate based SLN were prepared by hot high pressure homogenization and subjected to particle size, charge and inner structure analysis. 1% of each APG was sufficient to obtain SLN with a mean size between 150nm and 175nm and a narrow size distribution. The zeta potential in water was ∼ -50mV; the values in the original medium were distinctly lower, but still sufficient high to provide good physical stability. Physical stability at different temperatures (5°C, 25° and 40°C) was confirmed by a constant particle size over an observation period of 90 days in all dispersions. In comparison to SLN stabilised with classical surfactants, e.g. Polysorbate, APG stabilised SLN possess a smaller size, improved physical stability and contain less surfactant. Therefore, the use of APGs for the stabilization of lipid nanoparticles is superior in comparison to classical stabilizers. Further, the results indicate that the length of the alkyl chain of the APG influences the diminution efficacy, the final particle size and the crystallinity of the particles. APGs with short alkyl chain led to a faster reduction in size during high pressure homogenization, to a smaller particle size of the SLN and to a lower recrystallization index, i.e. to a lower crystallinity of the SLN. The crystallinity of the SLN increased with an increase in the alkyl chain length of APGs. Therefore, by using the tested APGs differing in the alkyl chain length, not only small sized and physically stable but also SLN with different sizes and crystallinity can be obtained. An optimised selection of these stabilizers might therefore enable the production of lipid nanoparticles with "tailor-made" properties.
    International Journal of Pharmaceutics 08/2014; · 3.99 Impact Factor
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    ABSTRACT: After use in oral pharmaceutical products, nanocrystals are meanwhile applied to improve the dermal penetration of cosmetic actives (e.g., rutin, hesperidin) and of drugs. By now, nanocrystals are only dermally applied made from poorly soluble actives. The novel concept is to formulate nanocrystals also from medium soluble actives, and to apply a dermal formulation containing additionally nanocrystals. The nanocrystals should act as fast dissolving depot, increase saturation solubility and especially accumulate in the hair follicles, to further increase skin penetration. Caffeine was used as model compound with relevance to market products, and a particular process was developed for the production of caffeine nanocrystals to overcome the supersaturation related effect of crystal growth and fiber formation - typical with medium soluble compounds. It is based on low energy milling (pearl milling) in combination with low dielectric constant dispersion media (water-ethanol or ethanol-propylene glycol mixtures) and optimal stabilizers. Most successful was Carbopol(®) 981 (e.g., 20% caffeine in ethanol-propylene glycol 3:7 with 2% Carbopol, w/w). Nanocrystals with varied sizes can now be produced in a controlled process, e.g., 660nm (optimal for hair follicle accumulation) to 250nm (optimal for fast dissolution). The short term test proved stability over 2 months of the present formulation being sufficient to perform in vivo testing of the novel concept.
    International Journal of Pharmaceutics 05/2014; · 3.99 Impact Factor
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    ABSTRACT: Polyhydroxy surfactants are nonionic ethylene oxide free stabilizers known for their complimentary dermatological properties and favorable environmental profile. The aim of this study was to develop solid lipid nanoparticles (SLN) stabilized with polyhydroxy surfactants varying in the chemical structure and to investigate the influence of the surfactants on the characteristics of the particles. Particles were produced by hot high pressure homogenization and the physico-chemical properties, e.g. contact angle, particle size, size distribution, zeta potential and crystallinity were determined. Results showed that the chemical structure of the surfactants influences the contact angle, particle size and crystallinity. Furthermore, the low surfactants concentration used (1% (w/w)) allowed the formation of the particles with a mean size below 200 nm, polydispersity index lower than 0.1 and sufficient physical stability for at least 6 months. As postulated by the zeta potential analysis stabilization ability of the surfactants was attributed to the superposition of electrostatic and steric effect which complement each other. All SLN formulations consisted of the same lipid matrix, but were found to possess different crystallinity indices. These differences are obviously created by the differences in the chemical structure of the surfactants. Therefore, the polyhydroxy surfactants investigated in this study can be judged to be novel suitable stabilizers for the formulation of well-skin tolerable SLN. The use of specific chemical structures of the surfactants can be used for the production of “tailor-made” SLN in the future.
    Colloids and Surfaces A Physicochemical and Engineering Aspects 03/2014; 444:15–25. · 2.11 Impact Factor
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    ABSTRACT: The ARTcrystal(®) process is a new approach for the production of drug nanocrystals. It is a combination of a special pre-treatment step with subsequent high pressure homogenization (HPH) at low pressures. In the pre-treatment step the particles size is already reduced to the nanometer range by use of the newly developed ART MICCRA rotor-stator system. In this study, the running parameters for the ART MICCRA system are systematically studied, i.e. temperature, stirring speed, flow rate, foaming effects, size of starting material, valve position from 0° to 45°. The antioxidant rutin was used as model drug. Applying optimized parameters, the pre-milling yielded already a nanosuspension with a photon correlation spectroscopy (PCS) diameter of about 650nm. On lab scale production time was 5min for 1L nanosuspension (5% rutin content), i.e. the capacity of the set up is also suitable for medium industrial scale production. Compared to other nanocrystal production methods (bead milling, HPH etc.), similar sizes are achievable, but the process is more cost-effective, faster in time and easily scale-able, thus being an interesting novel process for nanocrystal production on lab and industrial scale.
    International Journal of Pharmaceutics 02/2014; · 3.99 Impact Factor
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    ABSTRACT: Nanocrystals are meanwhile applied to increase the dermal penetration of drugs, but were applied by now only to poorly soluble drugs (e.g. 1-10 μg/ml). As a new concept nanocrystals from medium soluble actives were produced, using caffeine as model compound (solubility 16 mg/ml at 20°C). Penetration should be increased by a) further increase in solubility and b) mainly by increased hair follicle targeting of nanocrystals compared to pure solution. Caffeine nanocrystal production in water lead to pronounced crystal growth. Therefore the stability of nanocrystals in water-ethanol (1:9) and ethanol-propylene glycol (3:7) mixtures with lower dielectric constant D was investigated, using various stabilizers. Both mixtures in combination with Carbopol(®) 981 (non-neutralized) yielded stable nanosuspensions over 2 months at 4°C and room temperature. Storage at 40°C lead to crystal growth, attributed to too strong solubility increase, supersaturation and Ostwald ripening effects. Stability of caffeine nanocrystals at lower temperatures could not only be attributed to lower solubility, because the solubilities of caffeine in mixtures and in water are not that much different. Other effects such as quantified by reduced dielectric constant D, and specific interactions between dispersion medium and crystal surface seem to play a role. With the 2 mixtures and Carbopol(®) 981, a basic formulation composition for this type of nanocrystals has been established, to be used in the in vivo proof of principle of the new concept.
    European Journal of Pharmaceutics and Biopharmaceutics. 01/2014;
  • Biswadip Sinha, Rainer H Müller, Jan P Möschwitzer
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    ABSTRACT: Cavi-precipitation process is a combinative particle size reduction technology based on solvent-anti-solvent precipitation coupled high pressure homogenization (HPH). The cavi-precipiation can be used for the efficient production of drug nanocrystals (NC) with improved dissolution rate leading to better bioavailability. The work presented here demonstrates the advantage of cavi-precipitation process over the standard HPH processes and standard combination process (decoupled process) where precipitation is performed outside the homogenizer. The model compound ibuprofen (IBP) was solubilized in isopropanol (IPA) to constitute the solvent phase and mixed with the anti-solvent phase (0.1% (w/v) hydroxypropyl methylcellulose with 0.2% (w/v) sodium dodecyl sulphate) at different ratios to carry out the precipitation step. IBP-IPA-Water composition was selected from ternary diagram for a highly supersaturated zone to obtain smaller size particles. The mean particle size [d(0.5)] obtained by this process (300nm) was much smaller when compared to that obtained from the decoupled process (1.5μm). Optimization of the solvent-anti-solvent ratio and drug concentration was necessary to achieve a smaller particle size. PXRD and DSC results revealed that the solid state properties of the original IBP and the prepared NC samples by cavi-precipitation samples were similar.
    International Journal of Pharmaceutics 10/2013; · 3.99 Impact Factor
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    ABSTRACT: Abstract Objective: To prepare stable and easy to handle formulation of solid lipid nanoparticles (SLNs) by freeze-drying with or without cryoprotectants, as appropriate. Materials and methods: SLNs were freeze-dried without cryoprotectants or with cryoprotectants in quantities selected by freeze-thaw test (sucrose, glucose) or literature search (trehalose, maltose). Appearance, re-dispersability and size distribution of re-dispersed samples were evaluated. Results: SLN could be freeze-dried using 10% sucrose, trehalose or maltose. Trehalose was effective in protecting one of presented formulations that was already very stable on its own; its efficiency in protecting other two formulations was limited. Discussion: Our results are in line with various reports of successful freeze-drying of SLN, but considering the stability of original dispersions, no improvement was achieved. Conclusion: We confirmed that trehalose is among the most suitable cryoprotectant for SLN, however it did not improve shelf-life of the most stable formulation.
    Pharmaceutical Development and Technology 10/2013; · 1.33 Impact Factor
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    ABSTRACT: Abstract Nicergoline, a poorly soluble active pharmaceutical ingredient, possesses vaso-active properties which causes peripheral and central vasodilatation. In this study, nanocrystals of nicergoline were prepared in an aqueous solution of polysorbate 80 (nanosuspension) by using four different laboratory scale size reduction techniques: high pressure homogenization (HPH), bead milling (BM) and combination techniques (high pressure homogenization followed by bead milling HPH + BM, and bead milling followed by high pressure homogenization BM + HPH). Nanocrystals were investigated regarding to their mean particles size, zeta potential and particle dissolution. A short term physical stability study on nanocrystals stored at three different temperatures (4, 20 and 40 °C) was performed to evaluate the tendency to change in particle size, aggregation and zeta potential. The size reduction technique and the process parameters like milling time, number of homogenization cycles and pressure greatly affected the size of nanocrystals. Among the techniques used, the combination techniques showed superior and consistent particle size reduction compared to the other two methods, HPH + BM and BM + HPH giving nanocrystals of a mean particle size of 260 and 353 nm, respectively. The particle dissolution was increased for any nanocrystals samples, but it was particularly increased by HPH and combination techniques. Independently to the production method, nicergoline nanocrystals showed slight increase in particle size over the time, but remained below 500 nm at 20 °C and refrigeration conditions.
    Drug Development and Industrial Pharmacy 07/2013; · 1.54 Impact Factor
  • Jaime Salazar, Rainer H Müller, Jan P Möschwitzer
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    ABSTRACT: Standard particle size reduction techniques such as high pressure homogenization or wet bead milling are frequently used in the production of nanosuspensions. The need for micronized starting material and long process times are their evident disadvantages. Combinative particle size reduction technologies have been developed to overcome the drawbacks of the standard techniques. The H 42 combinative technology consists of a drug pre-treatment by means of spray-drying followed by standard high pressure homogenization. In the present paper, spray-drying process parameters influencing the diminution effectiveness, such as drug and surfactant concentration, were systematically analyzed. Subsequently, the untreated and pre-treated drug powders were homogenized for 20 cycles at 1500 bar. For untreated, micronized glibenclamide, the particle size analysis revealed a mean particle size of 772 nm and volume-based size distribution values of 2.686 μm (d50%) and 14.423 μm (d90%). The use of pre-treated material (10:1 glibenclamide/docusate sodium salt ratio spray-dried as ethanolic solution) resulted in a mean particle size of 236 nm and volume-based size distribution values of 0.131 μm (d50%) and 0.285 μm (d90%). These results were markedly improved compared to the standard process. The nanosuspensions were further transferred into tablet formulations. Wet granulation, freeze-drying and spray-drying were investigated as downstream methods to produce dry intermediates. Regarding the dissolution rate, the rank order of the downstream processes was as follows: Spray-drying > freeze-drying > wet granulation. The best drug release (90% within 10 minutes) was obtained for tablets produced with spray-dried nanosuspension containing 2% mannitol as matrix former. In comparison, the tablets processed with micronized glibenclamide showed a drug release of only 26% after 10 min. The H 42 combinative technology could be successfully applied in the production of small drug nanocrystals. A nanosuspension transfer to tablets that maintained the fast dissolution properties of the drug nanocrystals was successfully achieved.
    European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 04/2013; · 2.61 Impact Factor
  • Jaime Salazar, Rainer H Müller, Jan P Möschwitzer
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    ABSTRACT: The nanosizing of poorly soluble drugs as a formulation strategy can eventually enhance their dissolution rate and bioavailability. Standard comminution techniques such as high-pressure homogenization (HPH) or wet bead milling have limitations in reaching the desired mean particle size. Combinative methods have been developed to overcome these limitations. Combinations of a bottom-up step (freeze-drying or spray drying) with HPH (the so-called H 96 and H 42 technologies, respectively) are examples of combinative particle-size-reduction technologies. The precipitation step modifies the drug structure to obtain a brittle starting material for the following homogenization process. Previous experiments using the H 96 technology have shown a relation between the bottom-up conditions and the final particle size after the top-down step. Employing the H 42 process, the poorly soluble drug glibenclamide was dissolved in ethanol, containing different amounts of surfactant. The drug solution was then spray dried. Subsequently, the drug powders were homogenized using the HPH technique. The nanosuspensions produced with the spray-dried powders (high drug concentrations, standard surfactant concentration) had a smaller particle size and a narrower size distribution compared with the unmodified drug. The best sample had a 236 nm mean particle size (observed using photon correlation spectroscopy) and laser diffractometry values of 0.131 µm (D50) and 0.285 µm (D90) after 20 cycles of homogenization. The results were compared with the reduction effectiveness of a previous study employing the H 96 combinative process. Both combinative technologies can be successfully applied for the production of very small drug nanocrystals. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.
    Journal of Pharmaceutical Sciences 02/2013; · 3.13 Impact Factor
  • Biswadip Sinha, Rainer H Müller, Jan P Möschwitzer
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    ABSTRACT: The solubility dependent bioavailability problem has become a major hurdle in drug development processes. Drug nanocrystals have been widely accepted by the pharmaceutical industry to improve the bioavailability of poorly water soluble compounds. Top-down and bottom-up technologies are the two primary technical approaches of drug nanocrystal production. Though the top-down approach has been hugely successful on the commercial front, it has some inherent drawbacks that necessitate the emergence of alternate approaches. The bottom-up approach has not yet been established as a successful commercial technology. However, it has the potential to produce small size drug nanocrystals with less energy demanding processes. The bottom-up approach is commonly known as precipitation technique. It would be possible to stabilize particles at an early stage of precipitation and to generate drug nanocrystals. In the first part of this review article, we have discussed various bottom-up technologies that are currently in use. This has been followed by description and analysis of various process parameters that can affect the final particle size of the drug nanocrystals.
    International Journal of Pharmaceutics 01/2013; · 3.99 Impact Factor
  • Cornelia M Keck, Rainer H Müller
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    ABSTRACT: There is an increasing discussion about potential toxicity of nanoparticles (nanotoxicity). A classification system is proposed classifying the nanoparticles in 4 classes (I to IV) from low/no risk to high risk. It is based on the nanoparticle size (>/< 100 nm) and size-related differences in interaction with human cells, and on biodegradability/non-biodegradability in the body. This classification is superimposed by biocompatibility (B) and non-biocompatibility (NB) of the nanoparticle surface, resulting in a total of 8 classes from I-B (best tolerated) to IV-NB (highest potential risk). The classification should help as a guideline in pharmaceutical formulation development, but also as a guide for risk assessment in other product areas and environmental exposure.
    European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V 01/2013; · 3.15 Impact Factor
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    ABSTRACT: Curcumin, a naturally occuring polyphenolic phytoconstituent, is isolated from the rhizomes of Curcuma longa Linn. (Zingiberaceae). It is water insoluble under acidic or neutral conditions but dissolves in alkaline environment. In neutral or alkaline conditions, curcumin is highly unstable undergoing rapid hydrolytic degradation to feruloyl methane and ferulic acid. Thus, the use of curcumin is limited by its poor aqueous solubility in acidic or neutral conditions and instability in alkaline pH. In the present study, curcumin nanocrystals were prepared using high-pressure homogenization, to improve its solubility. Five different stabilizers [polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), d-α-tocopherol polyethylene glycol 1000 succinate (TPGS), sodium dodecyl sulfate (SDS), carboxymethylcellulose sodium salt] possessing different stabilization mechanism were investigated. The nanoparticles were characterized with regard to size, surface charge, shape and morphology, thermal property, and crystallinity. A short-term stability study was performed storing the differently stabilized nanoparticles at 4°C and room temperature. PVA, PVP, TPGS, and SDS successfully produced curcumin nanoparticle with the particle size in the range of 500-700 nm. PVA, PVP, and TPGS showed similar performance in preserving the curcumin nanosuspension stability. However, PVP is the most efficient polymer to stabilize curcumin nanoparticle. This study illustrates that the developed curcumin nanoparticle held great potential as a possible approach to improve the curcumin solubility then enhancing bioavailability. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.
    Journal of Pharmaceutical Sciences 10/2012; · 3.13 Impact Factor
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    ABSTRACT: This study aimed to examine the long-term physical stability of quercetin nanocrystals produced by three methods. Quercetin nanocrystals were prepared by high pressure homogenization, bead milling and cavi-precipitation. The nanocrystals produced by these methods were compared for particle size, saturation solubility and dissolution of the drug particles, and were subjected to stability testing. The X-ray diffraction study and microscopic pictures taken under polarized light indicated the crystalline nature of the nanocrystals produced by the three methods. As the crystalline state is relatively more stable than the amorphous state, a good physical stability was expected from the quercetin nanocrystals prepared. The high-pressure homogenized and bead-milled quercetin nanocrystals showed excellent physical stability when stored under refrigeration (4±2°C) and at room temperature (25±2°C) for 180 days. The dissolution properties were not significantly affected on storage at room temperature. However, increase in the storage temperature to 40±2°C led to physical instability. On the other hand, the cavi-precipitated quercetin nanocrystals exhibited a lower stability than the bead-milled and homogenized formulations and did not show the optimum zeta potential values as well. In the case of cavi-precipitated nanocrystals, recrystallization and agglomeration were responsible for the increasing particle size besides the Ostwald ripening phenomenon. The solvents used during cavi-precipitation might have competed with the surfactant for hydration leading to a partial dehydration of the surfactant, which subsequently affected the stability of the quercetin nanocrystals. High-pressure homogenized and bead-milled quercetin nanocrystals showed better physical stability than the cavi-precipitated ones. Freeze drying immediately after nanocrystal production can help to prevent their agglomeration and thus improve physical stability.
    The Journal of pharmacy and pharmacology. 10/2012; 64(10):1394-402.

Publication Stats

3k Citations
329.18 Total Impact Points

Institutions

  • 1992–2014
    • Freie Universität Berlin
      • • Institute of Pharmacy
      • • Division of Pharmaceutical Technology
      Berlín, Berlin, Germany
  • 2013
    • University of Camerino
      Camerino, The Marches, Italy
  • 2011–2012
    • Nanyang Technological University
      • School of Mechanical and Aerospace Engineering (MAE)
      Singapore, Singapore
  • 2010
    • University of Sharjah
      • College of Pharmacy
      Ash Shāriqah, Ash Shāriqah, United Arab Emirates
    • Universidade Fernando Pessoa
      • Faculty of Health Sciences
      Porto, Distrito do Porto, Portugal
  • 2009–2010
    • Charité Universitätsmedizin Berlin
      • Institute of Microbiology and Hygiene
      Berlin, Land Berlin, Germany
    • Central Drug Research Institute
      • Pharmaceutics Division (CDRI)
      Lucknow, Uttar Pradesh, India
  • 2007–2009
    • Mahidol University
      • Department of Pharmacy
      Bangkok, Bangkok, Thailand
  • 2005
    • Hochschule für Gesundheit und Medizin
      Berlín, Berlin, Germany